Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

You, Hui; Ge, Yamei; Zhang, Jian; Cao, Yibo; Xing, Jing; Su, Dongming; Huang, Yujie; Li, Min; Qu, Shen; Sun, Fei

doi:10.1242/jcs.198242

Cited by 26 publications

(27 citation statements)

References 30 publications

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“…Indeed, several molecular chaperones have been implicated in key steps during ENaC biogenesis, including subunit folding and channel assembly within the ER (30,31). Other factors regulate intracellular trafficking, plasma membrane insertion, and retrieval as well as both ER-associated and lysosome-mediated degradation of ENaC (32)(33)(34)(35)(36)(37). Together, this multistage machinery impacts the total number of channels (N) at the cell surface.…”

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confidence: 99%

Regulation of the epithelial Na+ channel by paraoxonase-2

Shi

Buck²,

Kinlough

et al. 2017

Journal of Biological Chemistry

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Paraoxonase-2 (PON-2) is a membrane-bound lactonase with unique anti-oxidative and anti-atherosclerotic properties. PON-2 shares key structural elements with MEC-6, an endoplasmic reticulum-resident molecular chaperone in MEC-6 modulates the expression of a mechanotransductive ion channel comprising MEC-4 and MEC-10 in touch-receptor neurons. Because mRNA resides in multiple rat nephron segments, including the aldosterone-sensitive distal nephron where the epithelial Na channel (ENaC) is expressed, we hypothesized that PON-2 would similarly regulate ENaC expression. We observed PON-2 expression in aquaporin 2-positive principal cells of the distal nephron of adult human kidney. PON-2 also co-immunoprecipitated with ENaC when co-expressed in HEK293 cells. When PON-2 was co-expressed with ENaC in oocytes, ENaC activity was reduced, reflecting a reduction in ENaC surface expression. MEC-6 also reduced ENaC activity when co-expressed in oocytes. The PON-2 inhibitory effect was ENaC-specific, as PON-2 had no effect on functional expression of the renal outer medullary potassium channel. PON-2 did not alter the response of ENaC to extracellular Na, mechanical shear stress, or α-chymotrypsin-mediated proteolysis, suggesting that PON-2 did not alter the regulation of ENaC by these factors. Together, our data suggest that PON-2 regulates ENaC activity by modulating its intracellular trafficking and surface expression.

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confidence: 99%

Regulation of the epithelial Na+ channel by paraoxonase-2

Shi

Buck²,

Kinlough

et al. 2017

Journal of Biological Chemistry

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“…Growing evidence now supports the ubiquitination of target proteins in the pathogenesis of a variety of diseases, including kidney injury . The attachment of ubiquitin (8.5 kDa) to a substrate protein requires three distinct enzymes and steps.…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence now supports the ubiquitination of target proteins in the pathogenesis of a variety of diseases, including kidney injury. 25,27,28 The attachment of ubiquitin (8.5 kDa) to a substrate protein requires three distinct enzymes and steps. The first step activates ubiquitin by forming a thioester linkage between the E1 ubiquitin-activating enzyme and the autophagy-related phagophore-formation transporter (APT).…”

Section: Discussionmentioning

confidence: 99%

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HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis

et al. 2020

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Injury of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. HUWE1, an E3 ubiquitin ligase, acts by participating in ubiquitination and degradation of its target proteins. However, the detailed mechanisms by which HUWE1 might regulate fibrosis in renal tubular epithelial cells have not been established. Here, the possible regulation of renal tubulointerstitial fibrosis by HUWE1 was investigated by examining the expression of HUWE1 and EGFR in unilateral ureteral obstruction (UUO) mice. Markedly consistent reciprocal changes in HUWE1 and EGFR expression were observed at the protein and mRNA levels in the kidney after UUO injury. Expression of HUWE1 inhibited TGF‐β‐induced injury to HK‐2 cells, while HUWE1 overexpression decreased the expression of EGFR. Further analysis indicated that HUWE1 physically interacted with EGFR and promoted its ubiquitination and degradation. HUWE1 expression also showed clinical relevance in renal disease, as it notably decreased in multiple types of clinical nephropathy, while EGFR expression significantly increased when compared to the normal kidney. Therefore, this study demonstrated that HUWE1, which serves as an E3 ubiquitin ligase specific for EGFR, promotes EGFR ubiquitination and degradation, thereby regulating EGFR expression and providing protection against kidney injury.

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“…We found that co-expression of PON3 reduced ENaC whole cell expression in FRT cells, suggesting that this trimeric channel is less stable in the presence of PON3. Molecular chaperones have important roles in ENaC quality control within the early secretory pathway (34,42,102). It is possible that PON3 facilitates proteasomal degradation of misfolded ENaC subunits.…”

Section: Discussionmentioning

confidence: 99%

Paraoxonase 3 functions as a chaperone to decrease functional expression of the epithelial sodium channel

Shi

Montalbetti

Wang

et al. 2020

Journal of Biological Chemistry

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The paraoxonase (PON) family comprises three highly conserved members: PON1, PON2, and PON3. They are orthologs of Caenorhabditis elegans MEC-6, an endoplasmic reticulum–resident chaperone that has a critical role in proper assembly and surface expression of the touch-sensing degenerin channel in nematodes. We have shown recently that MEC-6 and PON2 negatively regulate functional expression of the epithelial Na+ channel (ENaC), suggesting that the chaperone function is conserved within this family. We hypothesized that other PON family members also modulate ion channel expression. Pon3 is specifically expressed in the aldosterone-sensitive distal tubules in the mouse kidney. We found here that knocking down endogenous Pon3 in mouse cortical collecting duct cells enhanced Na+ transport, which was associated with increased γENaC abundance. We further examined Pon3 regulation of ENaC in two heterologous expression systems, Fisher rat thyroid cells and Xenopus oocytes. Pon3 coimmunoprecipitated with each of the three ENaC subunits in Fisher rat thyroid cells. As a result of this interaction, the whole-cell and surface abundance of ENaC α and γ subunits was reduced by Pon3. When expressed in oocytes, Pon3 inhibited ENaC-mediated amiloride-sensitive Na+ currents, in part by reducing the surface expression of ENaC. In contrast, Pon3 did not alter the response of ENaC to chymotrypsin-mediated proteolytic activation or [2-(trimethylammonium)ethyl]methanethiosulfonate–induced activation of αβS518Cγ, suggesting that Pon3 does not affect channel open probability. Together, our results suggest that PON3 regulates ENaC expression by inhibiting its biogenesis and/or trafficking.

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Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

Cited by 26 publications

References 30 publications

Regulation of the epithelial Na+ channel by paraoxonase-2

Regulation of the epithelial Na+ channel by paraoxonase-2

HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis

Paraoxonase 3 functions as a chaperone to decrease functional expression of the epithelial sodium channel

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